Asthma is a respiratory disease characterized by variable airways obstruction, airways inflammation and bronchial hyperresponsiveness (BHR). There are increases in asthma mortality and prevalence in the US, especially in African-Americans. Multiple studies suggest that both genetic and environmental factors are important in asthma susceptibility. The aim of the Collaborative Study of the Genetics of Asthma (CSGA) is to identify asthma susceptibility loci. The CSGA is composed of four centers (Johns Hopkins University, university of Chicago, University of Maryland, University of Minnesota, and a data coordinating center at Bowman Gray). At each center, families were ascertained through two siblings with asthma. All family members were characterized with spirometry, bronchial responsiveness to methacholine or reversibility testing, skin-tests and questionnaire data. The initial genome screen has been completed on the first 237 sib pairs from three racial groups (African-American, Caucasian, and Hispanic), and genotyping on the remaining family members and families will be completed before the start of the renewal proposal. Therefore, the initial aim of the CSGA to map susceptibility regions has been completed, with detection of several novel chromosomal regions, and replication of several regions previously linked to associated phenotypes. In order to determine the importance of these regions in asthma susceptibility, and the impact of environmental risk factors, we propose to 1) evaluate the evidence for linkage in the complete CSGA data using 2-point, multipoint and multilocus approaches for asthma and associated phenotypes (including BHR, total serum IgE and skin test reactivity to standardized allergens); 2)perform fine mapping studies of regions using additional genetic markers to obtain a <2 cM map; 3) identify candidate genes and novel sequence variants; and 4) characterize a patient population with asthma to study identified variants with respect to asthma severity and bronchial inflammation. These studies will allow US to identify asthma susceptibility genes and their variants, interactions with other genes and environmental risk factors, as well as provide insight for the development of improved treatment and ultimate prevention of asthma.